The age-related loss in skeletal muscle mass (sarcopenia) is associated with functional deficits and physical disability. Decreases in fiber size, and in contractile and metabolic capacity underlie the muscle weakness associated with senescence. Changes in gene expression with age represent a significant contribution to the functional defects. Newly developed oligonucleotide arrays are a powerful tool ideally suited for describing global changes in gene expression patterns with advance age. In the present application, we propose to examine in parallel the expression of thousands of genes in human skeletal muscle in response to aging using muscle biopsy samples and oligonucleotide-based DNA arrays. We propose to test the hypothesis that compared to young adult men, skeletal muscle from older healthy men will exhibit an upregulation of the stress response genes (heat shock response, DNA damage-inducible, oxidative stress-inducible), upregulation of genes associated with neuronal injury, and downregulation of the genes associated with energy metabolism (glycolysis, mitochondrial, and biosynthetic enzymes). In future work we will delineate the reversibility of age-associated changes by testing whether 12 weeks of progressive resistance training exercise will reverse the age-associated alterations in skeletal muscle gene expression. Alternatively, there may be age-related changes that are recalcitrant to "correction" or, new patterns of gene expression may result from training that counteract the functional deficits associated with aging. Differential gene expression with age and exercise will be analyzed by known gene functional category, and by similarity of gene expression change (i.e., cluster analysis). Genome- wide experiments will improve our understanding of biological processes by providing a comprehensive view of the molecular landscape in control vs. experimental tissue. The combined skills and expertise of Dr. Kandarian's and Fielding's laboratories lend themselves ideally to the study of the relationship between muscle function and genome-wide phenotypic changes. These investigators are invested in, and uniquely well suited to embark on this exciting collaboration using the expert application of molecular biological tools to the clinical problem of sarcopenia.